Retroviruses
Retroviruses are small, single-stranded positive-sense RNA viruses. A retroviral particle comprises two identical single-stranded positive sense RNA molecules. Their genome contains, among other things, the sequence of the RNA-dependent DNA polymerase, also known as reverse transcriptase. Many molecules of reverse transcriptase are found in close association with the genomic RNA in the mature viral particles. Upon entering a cell, this reverse transcriptase produces a double-stranded DNA copy of the viral genome, which is then inserted into the chromatin of a host cell. Once inserted, the viral sequence is called a provirus. Retroviral integration is directly dependent upon viral proteins. Linear viral DNA termini (the LTRs) are the immediate precursors to the integrated proviral DNA. There is a characteristic duplication of short stretches of the host's DNA at the site of integration.
Progeny viral genomes and mRNAs are transcribed from the inserted proviral sequence by host cell RNA polymerase in response to transcriptional, regulatory signals in the terminal regions of the proviral sequence, the long terminal repeats, or LTRs. The host cell's protein production machinery is used to produce viral proteins, many of which are inactive until processed by virally encoded proteases. Typically, progeny viral particles bud from the cell surface in a non-lytic manner. Retroviral infection does not necessarily interfere with the normal life cycle of an infected cell or organism. However, neither is it always benign with respect to the host organism. While most classes of DNA viruses can be implicated in tumorigenesis, retroviruses are the only taxonomic group of RNA viruses that are oncogenic. Various retroviruses, such as the Human Immunodeficiency Virus (HIV), which is the etiological agent responsible for acquired immune deficiency syndrome (AIDS) in humans, are also responsible for several very unusual diseases of the immune system of higher animals.
HIV INFECTION AND AIDS
Human Immunodeficiency Virus (HIV) is a member of the lentiviruses, a subfamily of retroviruses. Many retroviruses are well-known carcinogens. HIV per se is not known to cause cancer in humans or other animals, but it does present a formidable challenge to the host. The viral genome contains many regulatory elements which allow the virus to control its rate of replication in both resting and dividing cells. Most importantly, HIV infects and invades cells of the immune system; it breaks down the body's immune system and renders the patient susceptible to opportunistic infections and neoplasms. The immune defect appears to be progressive and irreversible, with a high mortality rate that approaches 100% over several years.
HIV-1 is trophic and cytopathic for T4 lymphocytes, cells of the immune system which express the cell surface differentiation antigen CD4, also known as OKT4, T4 and leu3. The viral tropism is due to the interactions between the viral envelope glycoprotein, gp120, and the cell-surface CD4 molecules (Dalgleish et al., Nature 312:763-767, 1984). These interactions not only mediate the infection of susceptible cells by HIV, but are also responsible for the virus-induced fusion of infected and uninfected T. cells. This cell fusion results in the formation of giant multinucleated syncytia, cell death, and progressive depletion of CD4 cells in AIDS patients. These events result in HIV-induced immunosuppression and its subsequent sequelae, opportunistic infections and neoplasms.
In addition to CD4+ T cells, the host range of HIV includes cells of the mononuclear phagocytic lineage (Dalgleish et al., supra), including blood monocytes, tissue macrophages, Langerhans cells of the skin and dendritic reticulum cells within lymph nodes. HIV is also neurotropic, capable of infecting monocytes and macrophages in the central nervous system causing severe neurologic damage. Macrophage/monocytes are a major reservoir of HIV. They can interact and fuse with CD4-bearing T cells, causing T cell depletion and thus contributing to the pathogenesis of AIDS.
ANTI-HIV DRUGS
Intensive efforts are currently under way to develop therapies to prevent or intervene in the development of clinical symptoms in HIV-infected individuals. For the most part, efforts have been focused on the use of nucleoside analogue drugs such as AZT (azidothymidine), and on other dideoxynucleoside derivatives such as ddA, ddT, ddI, and ddC. These drugs inhibit the viral enzyme reverse transcriptase, thereby inhibiting de novo infection of cells. However, once viral infection has been established within a cell, viral replication utilizes host cell enzymes. Thus, drugs which inhibit only reverse transcriptase tend to have limited effects. While the spread of free virus within the organism can be blocked, the mechanisms of syncytia formation and pathogenesis through direct intercelluar spread remain. Accordingly, there is a need to provide new anti-HIV drugs which are not limited to inhibiting reverse transcriptase as their mechanism of action.
In an effort to find new and more effective drugs for treating HIV infections, attention has turned to compounds found in plants or compounds modified from natural products. In particular, tannins have been investigated for their medicinal uses, and several elagitannins exhibit some anti-tumor and anti-HIV activity (Okuda et al., Planta Med. 55:(2) 117-122, 1989; Bokesch et al., J. Nat Prod. 56(7): 1123-1129, 1993). Unfortunately, reports of the inhibition of reverse transcriptase of the tannins show that many of these tannins have little or no activity against reverse transcriptase, and there is as yet no reliable means for predicting which of these compounds will be effective (Kakiuchi et al., J. Nat. Prod. 48(4): 614-621, 1985; Nonaka et al., J. Nat. Prod. 53(3):587-595, 1990; Nakashima et al., Antiviral Res. 18(1): 91-103, 1992; Weaver et al., Biochem Pharmacol. 43(11): 2479-2489, 1992; Kilkuskie et al., Bioorg. Med. Chem. Lett. 2(12): 1529-1534, 1992).
Many of the tannin-based compounds are biphenyl derivatives. Historically, biphenyl derivatives have been investigated for their utility in treating a variety of liver diseases. One anti-viral agent has been used for the treatment of hepatitis in China (Liu et al., Hepato-pharmacology of Fructus Schizandrae in Advances in Chinese Medical Materials Research, edited by Chang et al., pp 257-267). One compound disclosed therein, 4,4'-dimethoxy-5,6,5'6'-bimethylenedioxy-2,2'- dimethoxycarbonyl biphenyl (DDB), exhibited some anti-HIV activity, with an ED50 value of 5 microgram/ml and a TI of &gt;20.
Schinsandra chinensis (Chinese name: Wu-Wei-Zi) has long been used in China as an astringent and tonic. In the 1970's it was found to be effective against viral hepatitis, for lowering elevated SGPT levels, and as a protective agent for the liver when injured by chemical agents such as carbon tetrachloride. Further study indicated that schisandrin C, isolated from the seeds of Schinsandra chinensis, was an active principle. During the total synthesis of schisandrin C, a new anti-hepatic drug, 4,4'-dimethoxy-5,6,5'6,-bimethylenedioxi-2,2'-dimethoxycarbonyl biphenyl was discovered.
Shi-jie, in U.S. Pat. No. 4,868,207, discloses bis(methylenedioxy)biphenyl compounds of the formula ##STR1## wherein R is an alkyl group having 1 to 6 carbon atoms or a phenyl group, and R' is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms.
Iwasaki et al., in U.S. Pat. Nos. 5,103,023; 5,182,404 and 5,233,057; disclose biphenyl derivatives of the formula: ##STR2## wherein R.sup.1 is a substituted or unsubstituted aminocarbonyl group, aminothiocarbonyl group, a substituted or unsubstituted lower alkoxycarbonyl group, cyano group, or a group of the formula: ##STR3## one or two of R.sup.2 to R.sup.7 are hydrogen, and the remaining groups are the same or different and are each a lower alkoxy group, a phenyl(lower) alkoxy group or hydroxy group, or the adjacent two groups thereof combine to form a lower alkylenedioxy group, and Alk.sup.1 is a lower alkylene group, or a pharmaceutically acceptable salt thereof, which are useful for the prophylaxis and treatment of hepatic diseases.
Example 19 discloses 5,6,5',6'-dimethylenedioxy-2,2'-biphenylbis(thiocarboxamide), which is the only compound in this group with two dimethylenedioxy groups on the biphenyl derivative.
Kimura et al., in U.S. Pat. Nos. 4,849,448; 4,996,331; and 5,264,594; disclose biphenyl derivatives which can be used to treat hepatitis. The biphenyl derivative has the formula: ##STR4## wherein R.sub.0 and R.sub.1 independently stand for a lower alkyl group or R.sub.0 and R.sub.1 together represent a group O=C&lt;, R.sub.2 stands for an alkyl group having 1 to 3 carbon atoms, and R.sub.3 and R.sub.4 independently stand for a hydrogen atom or a lower alkyl group.
Matsuoka et al., in U. S. Pat. Nos. 4,904,694 and 4,987,240, disclose biphenyl derivatives which are used for moderating liver ailments and for treating hepatitis. These compounds have the formula: ##STR5##
wherein R.sub.1 and R.sub.2 stand for hydrogen or methyl.
Hirayama et al., U.S. Pat. No. 5,159,069, disclose sulfated tannins which have antiviral activity and reverse transcriptase inhibition which can be used to treat patients infected with viruses such as HIV.
Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited document is considered material to the patentability of the claims of the present application. All statements as to the date or representation as to the contents of these documents is based upon the information available to the applicant, and does not constitute any admission as to the correctness of the dates or contents of these documents.